Drug Regulation: Has the Worst Become the Norm?

A sad litany of new examples suggests the FDA has lost its ability to reason about risk.

A 2006 survey of biopharmaceutical companies’ views of FDA oversight, released last month, reveals problems. Biopharmaceuticals are drugs or medical devices made with the newest techniques of biotechnology, such as gene-splicing and monoclonal antibody technology. Unlike conventional drugs, which are usually small molecules produced via chemical synthesis, biopharmaceuticals come from living cells, such as bacteria, yeast or animal or human cells in tissue culture.

More than half [of the companies] said that the FDA “needs the most improvement” in “risk-based decision-making,” which is supposed to be its most essential stock in trade.

The study, by a biotechnology industry group and a major consulting firm, generally has been spun as portraying the regulatory environment as favorable and improving. Most news reports noted, for example, that 81 percent of the surveyed companies said the FDA was performing better since the 1997 advent of “user fees”—another name for a discriminatory tax on the inventors of new drugs—intended to speed up product reviews. But the reports ignored that more than a third of companies complained that the FDA had changed its position in the middle of the testing of a product, and more than half said that the FDA “needs the most improvement” in “risk-based decision-making,” which is supposed to be its most essential stock in trade.

Even if the current milieu is better than a decade ago (which, for the reasons discussed below, is doubtful), both the industry and consumers who need new drugs are in real trouble. In spite of increasingly more powerful and precise technologies for drug discovery, purification and production during the past twenty years, development costs have skyrocketed. According to the latest data (2006) from the TuftsCenter for the Study of Drug Development, on average it takes more than eight years and costs $1.2 billion to develop a biopharmaceutical. Of this amount, capitalized out-of-pocket preclinical costs are approximately $615 million, while clinical testing accounts for $626 million.

Why the huge costs and lengthy development times, which exceed even those for conventional drugs?Regulatory excesses, for the most part. Regulators are inflexible and inconsistent and keep raising the bar for approval, especially for innovative, high-tech products.

However, contrary to perceptions that regulatory oversight might have become lax, drug regulation in the United States in recent years has actually become progressively more risk-averse…

However, contrary to perceptions that regulatory oversight might have become lax, drug regulation in the United States in recent years has actually become progressively more risk-averse, as the FDA has steadily made it more difficult to initiate and perform the clinical testing of new drugs. Recent criticism from Congress, the media and others regarding drug safety has caused an already risk-averse agency to become even more conservative and defensive in its decision-making. The FDA has been requiring ever larger numbers of patients in clinical trials; its demands for post-marketing clinical trials have proliferated wildly; and “risk management” plans for newly approved drugs have been inconsistently applied, punitive and often more appropriate for weapons-grade plutonium than prescription drugs.

Regulators’ moving the goalposts in the middle of the game is particularly vexing for drug developers. In September 2006, Genentech announced that approval of its colon cancer drug Avastin for breast cancer would be delayed at least a year because of requests from the FDA for additional data. The company said that regulators appeared to be increasing the stringency of requirements for certain types of clinical trials and had arbitrarily demanded that its trials be “audited and summarized” in a way different from that earlier agreed upon with regulators.

Another recent and particularly problematic example involves Somaxon Pharmaceuticals’ testing of an already-approved drug, doxepin, for a new indication. The drug, approved for the treatment of depression since 1969, is being tested in very low doses for use as a sleeping pill. The FDA initially assured the company that it could begin human clinical trials without first doing animal tests because of doxepin’s long history of use in people and because Somaxon was using a dose less than one-tenth that used to treat depression. However, in May 2006, after having completed several clinical trials, while the company was meeting with the FDA to discuss the submission of a New Drug Application, regulators unexpectedly asked for a full battery of testing in animals. Animal testing is usually considered to be “pre-clinical,” so it is difficult to understand the logic of animal testing for an almost forty-year-old drug that is undergoing trials for a new indication, and at a far lower dose than it is normally used.

In addition, a number of drugs previously granted marketing approval in Europe have received “approvable,” instead of approval, letters from the FDA, meaning that additional data is required before the drug can be marketed. These include Sanofi-Aventis’ Acomplia for weight loss and cessation of smoking, NPS Pharmaceuticals’ Preos for osteoporosis and Encysive Pharmaceuticals’ Thelin for pulmonary hypertension.

In the review of cancer drugs in particular, FDA reviewers and managers frequently are characterized as inadequately prepared for meetings with industry scientists and insensitive to the needs of dying patients.

Many new targeted therapies are difficult to assess with traditional clinical trial designs or endpoints. For example, a drug intended to arrest or eliminate cancer by boosting the patient’s immune system might be most efficacious in early stage cancers when the tumor load is low and the patient is not debilitated. Thus, if the company were to adopt a clinical design that called for recruiting and treating only patients with advanced cancers, one would expect to see reduced efficacy. This kind of situation, in which there is a high level of novelty and uncertainty, argues for greater flexibility both in clinical trial design and in reaching agreement on what constitutes “efficacy,” but instead the FDA has been risk-averse and defensive, sometimes intransigent. In the review of cancer drugs in particular, FDA reviewers and managers frequently are characterized as inadequately prepared for meetings with industry scientists and insensitive to the needs of dying patients.

Times are tough for drug development, and they are getting worse. Beleaguered regulators are in a risk-averse, defensive mode. The Congress has shirked its responsibility to ensure that innovation and ingenuity in drug development will flourish. If biopharmaceutical companies are not complaining loudly, the worst has become the norm.

Henry I. Miller, a physician and fellow at Stanford University’s Hoover Institution, headed the FDA’s Office of Biotechnology from 1989 to 1993. He is the author, most recently, of “The Frankenfood Myth.”